Epigenetic modification is a major contributor to determining individuals'phenotype with genotype and environment. A single human genome with an identical sequence can derive several different versions of the epigenetically modified genome, epigenome, which are accountable for interindividual variations in the healthy life and disease susceptibility of humans. Recent studies have indicated that environmental exposures may be a significant contributor to these epigenetic variations. However, the molecular bases of epigenetic variations and subsequent functional outcomes that may be caused by environmental exposures are largely unknown. Thus, as an initial step challenging these questions, this project proposes to identify and characterize the potential contributions of one type of mobile DNA elements to the epigenetic variations. According to the results from the studies on two mutant mice, viable yellow agouti (Avy) and axin-fused kinky (Axinfu), one type of repetitive elements, retrotransposons, display unusual interindividual variations in their DNA methylation levels and associated phenotypes. This has prompted us to identify retrotransposons with similar features from the human and mouse genomes. Preliminary analyses revealed that about 3% of the entire transcriptomes of human and mouse may be driven by retrotransposons, and that some of these retro elements likely have similar features as the two mouse loci: variable levels of DNA methylation and subsequent transcriptional interference to nearby genes. Thus, we hypothesize that mammalian retrotransposons may be one of the major classes of DNA elements that are epigenetically labile and susceptible to environmental exposures, and that some of these identified retrotransposons may contribute to variations in the human epigenome. These hypotheses will be tested with the following aims: 1) characterization of the identified retrotransposon-driven transcripts in terms of their epigenetic variations and functional outcomes, and 2) demonstration of epigenetic metastability of the identified retrotransposons against environmental interventions. The information from the current project will be very helpful for our understanding of epigenetic variations and related phenotypic differences observed among human populations. PUBLIC HEALTH RELEVANCE: Epigenetic variations are responsible for many disease susceptibilities that are often observed among different human populations. This project aims to identify and characterize one of mammalian repetitive DNA elements, retrotransposons, as a main source to the epigenetic variations in the human and other mammalian genomes.